Jane Pritchard

Risk of relapse of Guillain-Barré syndrome or chronic inflammatory demyelinating polyradiculoneuropathy following immunisation

Reports of the rare occurrence of Guillain-Barre syndrome (GBS) or chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) following immunisation1 and recurrence of symptoms following subsequent immunisation2 have given rise to concern over the safety of vaccine administration in this patient group. Similar concerns have been addressed and dismissed in patients with multiple sclerosis,3 but no such information exists for inflammatory neuropathy. To provide more information about vaccine safety in GBS and CIDP we audited the recurrence of neurological symptoms following immunisation. The Guillain-Barre Syndrome Support Group, a British patient organisation, posted 3000 questionnaires to its members, asking them to identify their illness, record all immunisations administered after their illness, and describe any symptoms within six weeks of immunisation suggestive of recurrence of GBS or worsening of CIDP. All but one of the patients who reported neurological symptoms after immunisation were contacted by telephone to confirm their history and to grade their symptoms using the modified Rankin scale.4 For the patient who could not be contacted by telephone, the patients consultant neurologist provided the information. Questionnaires were sent to the general practitioner for each patient who reported a “relapse” to confirm which vaccine had been administered. A total of 1114 patients (37.1%) completed the questionnaires, of whom 927 had had …

A randomized controlled trial of recombinant interferon-beta 1a in Guillain-Barre syndrome

The authors recruited 19 nonambulant patients with Guillain-Barré syndrome into a pilot, double-blind, randomized, placebo-controlled safety trial of interferon beta 1a (IFNβ-1a) (Rebif). Participants received IFNβ-1a or placebo subcutaneously three times weekly, 22 μg for the first week and then 44 μg for up to 24 weeks, in addition to IV immunoglobulin (IVIg). IFNβ did not have any unexpected interaction with IVIg and there was no significant difference in rate of improvement.

Immune responses to myelin proteins in Guillain–Barré syndrome

Background: Potential target autoantigens in the demyelinating form of Guillain–Barré syndrome (GBS) include the myelin proteins PMP22, P0 and P2. Methods: We investigated immunoreactivity to P0, P2 and PMP22 proteins in 37 patients with GBS and 32 healthy controls. Results: Antibodies to PMP22 or P0 peptides were detected at presentation in only 5 out of 37 patients. In ELISPOT assays, blood mononuclear cells from 15 out of 24 patients with GBS, but none of the control subjects, produced interleukin-10 (IL-10) in response to peptides from proteins P0, P2 or PMP22 (p = 0.0003). The cells from only two patients produced interferon-γ (IFNγ). The cells from 11 patients with GBS had increased IL-10 responses to peptides representing sequences from the extracellular domains of PMP22 before intravenous immunoglobulin (IVIg) treatment (p = 0.006). The cells from 11 patients with GBS, including 7 who responded to the extracellular domains of PMP22, had increased IL-10 responses to the intracellular domain of P0 before (p = 0.005) and those from 9 patients after they had been treated with IVIg (p = 0.01). Conclusions: Antibodies to P0 and PMP22 protein peptides do occur in GBS but are uncommon. Circulating mononuclear cell IFNγ responses to P0, P2 and PMP22 myelin protein peptides are rare, but IL-10 responses occur significantly more often than in normal subjects. They might be part of a harmful pathogenetic process or represent a regulatory response.

Reduced circulating CD4+CD25+ cell populations in Guillain–Barré syndrome

Guillain-Barré syndrome (GBS) is a monophasic inflammatory disease considered to be due to autoimmunity. In order to test the hypothesis that the disease is associated with a perturbation of the circulating lymphoid cell population, we tested the mononuclear cells from the venous blood of 21 patients with Guillain-Barré syndrome (GBS) and 20 healthy controls by flow cytometry. The proportions and numbers of B and T lymphocytes, and CD4, CD8, double negative and gammadelta T cell subsets and numbers of monocytes were not significantly different in the patients compared with the controls. However, the number and proportion of CD4+CD25+ cells were reduced in acute GBS (mean number 61.7 cells/microl, 95% CI 42.9-80.4 and mean percentage 4.6%, 95% CI 3.8-5.4) compared with controls (mean number 99.8 cells/microl, 95% CI 74.7-124.9, p=0.02, and mean percentage 6.0%, 95% CI 4.9-7.1%, p=0.037). In addition, in GBS patients, the number and proportion of CD4+ T cells expressing CD25+ and HLA-DP, DQ, DR (mean number 11.9 cells/microl, 95% CI 7.6-16.1 and mean percentage 0.8%, 95% CI 0.5-1.1%) was lower than in healthy controls (23.5 cells/microl, 95% CI 16.4-30.6, p=0.01, and mean percentage 1.4%, 95% CI 1.1-1.8%, p=0.005. Since CD4+CD25+ cells include cells with special immunoregulatory functions, further investigation of this phenomenon and its relation to possible loss of regulatory T cell function in GBS is warranted.

Haemophilus influenzae as a possible cause of Guillain–Barré syndrome

Recent reports have contained conflicting results on the relationship between antecedent Haemophilus influenzae infection and Guillain-Barré syndrome (GBS). To investigate the prevalence of H. influenzae infection in GBS patients in a British population, we carried out a retrospective study with 62 consecutive GBS patients and 63 normal controls of similar age and sex. Whole bacteria of both encapsulated and nonencapsulated strains of H. influenzae were employed as antigens in an enzyme-linked immunosorbent assay (ELISA) for anti-H. influenzae IgG, IgM and IgA antibodies. Elevated antibodies of two or three classes were found in one GBS patient and none in the normal controls. Six GBS patients had IgG antibodies against nonencapsulated H. influenzae compared with only one in the normal control group (p=0.06). Western blot for IgG antibody showed that all the sera with IgG antibodies recognized the lipopolysaccharide (LPS) of both strains of H. influenzae. Antiganglioside GM1 antibody was not associated with anti-H. influenzae antibody in our study. Absorption with encapsulated or nonencapsulated H. influenzae, Campylobacter jejuni and Escherichia coli before testing on Western blot showed that only nonencapsulated H. influenzae absorbed the anti-LPS antibodies. In conclusion, there is a possible but rare association of GBS with nonencapsulated H. influenzae in the UK.

EponymGuillain-Barré syndrome

Guillain-Barré syndrome has now become recognized as a clinical syndrome that may be due to several pathological entities, consisting of an acute inflammatory demyelinating polyradiculoneuropathy as well as an acute motor axonal neuropathy. Campylobacter jejuni infection is a common preceding event and, together with anti-ganglioside GM1 antibodies, is associated with axonal damage and a poor outcome. The mechanism by which such antibodies damage axons is not clear. The Miller Fisher syndrome is very closely associated with antibodies to ganglioside GQ1b that may be important in pathogenesis. Treatment of Guillain-Barré syndrome with intravenous immunoglobulin appears to be as effective as plasma exchange in one controlled trial. Two small series have reported a high incidence of early relapses following intravenous immunoglobulin, and its efficacy is being reexamined in a further controlled trial.

Apolipoprotein E genotypes and clinical outcome in Guillain-Barré syndrome

Background: Polymorphism of the gene encoding the cholesterol transport protein apolipoprotein E (APOE, gene; apoE, protein), known to be involved in axonal regeneration and remyelination, influences outcome after a variety of central nervous system disorders. Apolipoprotein E gene polymorphisms could affect recovery from Guillain-Barré syndrome. Objective: To correlate APOE genotypes with residual disability and degree of improvement in Guillain-Barré syndrome, assessed one year after presentation Methods: 91 patients with the syndrome were recruited from southeast England and their APOE genotypes were determined. Results: There were no clear differences in APOE genotype or allele frequencies when comparing the 91 patients with controls, nor when comparing 81 patients with good outcome and 10 with poor outcome. Conclusions: APOE genotype did not influence susceptibility to Guillain-Barré syndrome or recovery from it. This may be because our sample size of 91 was not sufficiently large to detect small differences in recovery associated with different APOE genotypes, or because cholesterol transportation is not a crucial rate limiting step in peripheral nerve regeneration.

Novel therapeutic approaches to Guillain-Barré syndrome

Guillain-Barré syndrome is an autoimmune disease which occurs throughout the world. Whilst the majority of patients can expect a reasonable recovery, about 10% die and 10% are left disabled with current therapy. The standard treatment is a five day course of iv. immunoglobulin, given at a dose of 0.4 g/kg/day, with plasma exchange as an equally efficacious alternative. Steroids are ineffective in Guillain-Barré syndrome. All new potential therapeutic agents need to be tested in addition to the standard agents available. Future potential therapies are suggested by the study of the animal model experimental autoimmune neuritis in the Lewis rat. Whilst in theory it is possible to target the different stages of the immune response, in practice not all of the steps at which experimental autoimmune neuritis can be prevented will be translatable to human Guillain-Barré syndrome. This is because Guillain-Barré syndrome probably presents after the immune reaction has been ongoing for some time and therefore early aspects of the immune response cannot be prevented. Many of the possible measures would have widespread immunosuppressive effects which would be unacceptable to patients. Interfering with the immune response by attempting to block antigen binding or inducing tolerance may not be practical, owing to the possibility of exacerbating disease. Once we have a more thorough understanding of the pathogenesis of Guillain-Barré syndrome, then immune-specific therapy for Guillain-Barré syndrome may become a possibility, rather than general immunosuppressive measures. Trials of β-interferon and of a combination of steroid and iv. immunoglobulin are underway. A trial of a second course of iv. immunoglobulin is planned.

Intravenous Immunoglobulin – How to use it

WHAT IS IT? The immunoglobulin used in intravenous immunoglobulin (IVIg) is prepared from the pooled plasma from about 8000 blood donors. Plasma purification includes steps to remove viruses. Donors at risk for transfusion-related viruses are excluded and IVIg consists almost entirely of IgG with traces of IgM, IgA and soluble plasma factors including cytokines. Its initial use was as replacement therapy in hypogamma-globulinaemia. Its success in treating autoimmune thrombocytopenic purpura led to its use in other immune-mediated diseases. HOW DOES IT WORK? We do not really know. There are many proposed mechanisms. Different, possibly multiple, mechanisms may apply in different diseases (Fig. 1). WHO NEEDS IT? Guillain–Barré Syndrome (GBS) and Kawasaki disease are the only neurological conditions licensed for IVIg treatment in the United Kingdom. The strength of the evidence for the use of IVIg in other neurological conditions varies. Consensus does not exist. Tables 1, 2 and 3

Characterization of a monoclonal antibody specific for human peripheral myelin protein 22 and its use in immunohistochemical studies of the fetal and adult nervous system.

Abstract  We produced a mouse monoclonal antibody using cDNA and peptide immunization against the putative second extra‐cellular domain of human peripheral myelin protein 22 (PMP22). It reacted specifically with human PMP22 and not with other human myelin proteins and did not react with bovine, rat, or mouse PMP22. The antibody stained the compact myelin of human peripheral nerve motor and sensory axons and did not stain central nervous system tissue. PMP22 reactivity was detected in the spinal roots of the human fetus at 19–20 weeks of gestation. The staining pattern of the PMP22 antibody resembled that of a monoclonal antibody directed against the myelin protein zero.